Quinuclidine derivatives as squalene synthase inhibitors

ABSTRACT

Compounds of formula (I) and their pharmaceutically acceptable salts in which R 1  is hydrogen or hydroxy; R 2  is hydrogen; or R 1  and R 2  are joined together so that CR 1  --CR 2  is a double bond; X is selected from --CH 2  CH 2  --, --CH═CH--, --C≡C--, --CH 2  O--, --OCH 2  --, --CH 2  NH--, --NHCH 2  --, --CH 2  CO--, --COCH 2  --, --N═CH--, --CH═N--, --CH 2  S-- and --SCH 2  -- (wherein the sulphur atom in the latter two groups may optionally bear one or two oxygen atoms); Ar is a heterocyclic moiety containing up to three heteroatoms independently selected from nitrogen, oxygen and sulphur, and wherein Ar may optionally be unsubstituted or may bear one or more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, di-alkylamino, N-alkylcarbamoyl, di-N,N-alkylcarbamoyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, halogenoalkyl, alkanoylamino, ureido, N&#39;-alkylureido, alkanoyl and oxime derivatives thereof and O-alkyl ethers of said oxime derivatives; are inhibitors of squalene synthase and hence useful in treating medical conditions in which a lowering of cholesterol is beneficial. Processes preparing these derivatives, pharmaceutical compositions containing them are also described together with their use in medecine.

This application is a 371 of PCT/GB93/02617, Dec. 21, 1993.

This invention concerns heterocyclic-compounds which are useful ininhibiting squalene synthase, processes for their preparation andpharmaceutical compositions containing them. The present invention isalso concerned with methods of using such heterocyclic compounds intreating diseases and medical conditions where inhibition of squalenesynthase is desirable, for example in treating diseases or medicalconditions such as hypercholesterolemia and atherosclerosis.

Several different classes of compounds have been reported to possess thecapability of being able to lower cholesterol levels in blood plasma.For example agents which inhibit the enzyme HMG CoA reductase, which isessential for the production of cholesterol, have been reported toreduce levels of serum cholesterol. Illustrative of this class ofcompounds is the HMG CoA reductase inhibitor known as lovastatin whichis disclosed in U.S. Pat. No. 4,231,938. Other agents which are reportedto lower serum cholesterol include those which act by complexing withbile acids in the intestinal system and which are hence termed "bileacid sequestrants". It is believed that many of such agents act bysequestering bile acids within the intestinal tract. This results in alowering of the levels of bile acid circulating in the enteroheptaticsystem and promoting replacement of bile acids by synthesis in the liverfrom cholesterol which results in an upregulation of the hepatic LDLreceptor and hence in a lowering of circulating blood cholesterollevels.

Squalene synthase (also referred to in the art as squalene synthetase)is a microsomal enzyme which catalyses the first committed step ofcholesterol biosynthesis. Two molecules of farnesyl pyrophosphate (FPP)are condensed in the presence of the reduced form of nicotinamideadenine dinucleotide phosphate (NADPH) to form squalene. The inhibitionof this committed step to cholesterol should leave unhinderedbiosynthetic pathways to ubiquinone, dolichol and isopentenyl t-RNA.Elevated cholesterol levels bare known to be one of the main riskfactors for ischaemic cardiovacsular disease. Thus, an agent whichinhibits squalene synthase should be useful in treating diseases andmedical conditions in which a reduction in the levels of cholesterol isdesirable, for example hypercholesterolemia and atherosclerosis.

Thus far, the design of squalene synthase inhibitors has concentrated onthe preparation of analogues of the substrate farnesyl pyrophosphate(FPP), and hence on compounds which contain phosphorus groups. Forexample, the preparation of phosphorous-containing squalene synthaseinhibitors is reported in published European Patent Application No.409,181; and the preparation of isoprenoid(phosphinylmethyl)phosphonates as inhibitors of squalene synthase isreported by Biller et al, J. Med. Chem., 1988, 31, 1869. Quinuclidinederivatives are reported in, for example, EP 458,214 to be muscarinicagonists. Recently, certain quinuclidine derivatives have been reported(WO 92/15579 and U.S. Pat. No. 5,135,935) to inhibit squalene synthase.

The present invention is based on the discovery that certainheterocyclic compounds are inhibitors of squalene synthase, and arehence useful in treating diseases and medical conditions in whichinhibition of squalene synthase is desirable.

According to the present invention there is provided a compound offormula I (formula set out hereinafter together with the other chemicalformulae referred to herein in Roman numerals), or a pharmaceuticallyacceptable salt thereof, wherein:

R¹ is hydrogen or hydroxy;

R² is hydrogen; or

R¹ and R² are joined together so that CR¹ --CR² is a double bond;

X is selected from --CH₂ CH₂ --, --CH═CH--, --C≡C--, --CH₂ O--, --OCH₂--, --CH₂ NH--, --NHCH₂ --, --CH₂ CO--, --COCH₂ --, --N═CH--, --CH═N--,--CH₂ S-- and --SCH₂ -- (wherein the sulphur atom in the latter twogroups may optionally bear one or two oxygen atoms);

Ar is a heterocyclic moiety containing up to three heteroatomsindependently selected from nitrogen, oxygen and sulphur; and wherein Armay optionally be unsubstituted or may bear one or more substituentsindependently selected from halogeno, hydroxy, amino, nitro, cyano,carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino, di- (1-6C)alkyl!amino,N-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno-(1-6C)alkyl, (1-6C)alkanoylamino, ureido,N'-(1-6C)alkylureido, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives;

provided that when R¹ is hydroxy, X is not selected from --OCH₂ --,--N═CH--, --NHCH₂ -- and --SCH₂ -- (optionally bearing one or two oxygenatoms on sulphur); and that when R¹ and R² are both hydrogen, X is --CH₂O--, --OCH₂ --, --CH₂ S-- or --SCH₂ (wherein the sulphur atom in thelatter two groups optionally bears one or two oxygen atoms) then Ar isnot a 5, 6 or 7 membered heteroaryl moiety.

It will be understood that when formula I compounds contain a chiralcentre, the compounds of the invention may exist in, and be isolated in,optically active or racemic form. The invention includes any opticallyactive or racemic form of a compound of formula I which possesses thebeneficial pharmacological effect of inhibiting squalene synthase. Thesynthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example by,resolution of a racemic form, by synthesis from optically activestarting materials or by asymmetric synthesis.

It will also be understood that, insofar as certain of the compounds ofthe formula I may exhibit the phenomenon of tautomerism, for example acompound of formula I in which Ar bears a hydroxy substituent, thepresent invention includes any tautomeric form of a compound of formulaI which possesses the beneficial pharmacological effect of inhibitingsqualene synthase.

It is also to be understood that generic terms such as "alkyl" includeboth the straight chain and branched chain groups such as butyl andtert-butyl. However, when a specific term such as "butyl" is used, it isspecific for the straight chain or "normal" butyl group, branched chainisomers such as "t-butyl" being referred to specifically when intended.

It will also be appreciated that oxime derivatives of the (1-6C)alkanoylgroup will comprise aldoximes and ketoximes of formula --C(Ra)═NOH (Rais H or alkyl), and the O-alkyl ethers of these oximes will have theformula --C(Ra)═NORb (Ra is H or alkyl, and Rb is alkyl).

It will be appreciated that when R¹ and R² are joined so that CR¹ --CR²is a double bond, the quinuclidine moiety in formula I will comprise the2,3-dehydroquinuclidine moiety shown in formula Ia.

Ar, the heterocyclic moiety, encompases monocyclic aromatic heterocycleswhich contain (in addition to carbon atoms) one, two or threeheteroatoms selected from nitrogen, oxygen and sulphur; bicyclicaromatic heterocycles of about 8 to 10 ring atoms and containing (inaddition to carbon atoms) one, two or three heteroatoms selected fromnitrogen, oxygen and sulphur, and in particular, benz-derivatives ofsaid monocyclic aromatic heterocycles; as well as bicyclic heterocycleswhich consist of a non-aromatic 5-membered or 6-membered heterocyclicring containing (in addition to carbon atoms) one, two or threeheteroatoms selected from nitrogen, oxygen and sulphur which is fused toa benzene ring. It will be appreciated that the heterocyclic moiety maybe attached to Ar¹ through any available ring atom.

Suitable values for Ar will therefore include, for example, an aromatic5-membered or 6-membered heterocyclic ring containing one, two or threeheteroatoms selected from nitrogen, oxygen and sulphur, and an aromatic5-membered or 6-membered heterocyclic ring containing one, two or threeheteroatoms selected from nitrogen, oxygen and sulphur which is fused toa benzene ring; or a non-aromatic 5-membered or 6-membered heterocyclicring containing one, two or three heteroatoms selected from nitrogen,oxygen and sulphur fused to a benzene ring.

A particular value for X is, for example, --CH₂ CH₂ --, --CH═CH--,--C≡C--, CH₂ O, --CH₂ NH--, --NHCH₂ --, --CH₂ CO-- or --COCH₂ --. A moreparticular value for X is, for example, --CH₂ CH₂ --, --CH═CH--, --C≡C--or --CH₂ O.

A particular value for an optional substituent which may be present onAr, is, for example,

for alkyl; (1-4C)alkyl, such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl or sec-butyl;

for alkenyl; (2-4C)alkenyl, such as allyl, prop-2-enyl, but-2-enyl or2-methyl-2-propenyl;

for alkynyl; (2-4C)alkynyl, such as prop-2-ynyl or but-2-ynyl;

for alkoxy; (1-4C)alkoxy, such as methoxy, ethoxy, propoxy, isopropoxyor butoxy;

for alkylamino; (1-4C)alkylamino, such as methylamino, ethylamino,propylamino or butylamino;

for di-alkylamino; di-(1-4C)alkylamino, such as dimethylamino,diethylamino, methylpropylamino or dipropylamino;

for alkylcarbamoyl; N-methylcarbamoyl, N-ethylcarbamoyl orN-propylcarbamoyl;

for di-alkylcarbamoyl; di-(1-4C)alkylcarbamoyl, such asN,N-dimethylcarbamoyl or N,N-diethylcarbamoyl;

for alkoxycarbonyl; methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;

for alkylthio; methylthio, ethylthio, propylthio, isopropylthio orbutylthio;

for alkylsulphinyl; methylsulphinyl, ethylsulphinyl, propylsulphinyl,isopropylsulphinyl or butylsulphinyl;

for alkylsulphonyl; methylsulphonyl, ethylsulphonyl, propylsulphonyl,isoproylsulphonyl or butylsulphonyl;

for halogeno; fluoro, chloro, bromo or iodo;

for halogenoalkyl; halogenoalkyl containing one, two or three halogroups selected from fluoro, chloro, bromo and iodo and an alkyl groupselected from methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl andsec-butyl, (in particular fluoromethyl, difluoromethyl ortrifluoromethyl);

for alkanoyl; formyl, acetyl, propionyl and butyryl;

for alkylureido; N'-methylureido, N'-ethylureido, N'-propylureido,

N'-isoprpoylureido, N'-butylureido,

for O-(1-6C)alkyl ethers of alkanoyl oximes; methyl, ethyl, propyl,isopropyl and butyl esters

for alkanoylamino; formamido, acetamido, propionamido, iso-propionamido,butyramido or iso-butyramido.

Particular values for Ar include, for example, furyl, pyrrolyl, thienyl,pyridyl, pyrazinyl, primidinyl, pyridazinyl, imidazolyl, oxazolyl,isooxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, benzfuranyl, quinolyl, isoquinolyl, benzimidazolyl,indolyl, benzdihydrofuranyl, benzodioxolyl (such as 1,3-benzodioxolyl),and benzdioxanyl (such as 1,4-benzdioxanyl).

In general, it is preferred that Ar is optionally unsubstituted orsubstituted by one, two or three substituents independently selectedfrom those mentioned above.

In general it is preferred, for example, that R¹ is hydroxy and R² ishydrogen.

In general it is preferred, for example, That X is selected from--CH═CH--, --C≡C-- and --CH₂ O--, especially --C≡C--.

It is generally preferred, for example, that Ar is an aromatic5-membered or 6-membered heterocyclic ring containing (in addition tocarbon atoms) one, two or three heteroatoms selected from nitrogen,oxygen and sulphur which is optionally fused to a benzene ring. Morepreferably, Ar is a pyridyl or quinolyl moiety (especially pyridyl).

In general it is preferred, for example, that Ar may optionally bear oneor more substituents selected from halogeno, hydroxy, nitro,(1-6C)alkyl, (2-6C)alkenyl, (1-6C)alkoxy, (1-6C)alkanoylamino,halogeno-(1-6C)alkyl, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oximes.

Values of Ar of particular interest include, for example, pyridyl,pyrazinyl, primidinyl, pyridazinyl and imidazolyl (especially pyridyl).

More particular values for Ar include, for example, 2-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 5-pyrimidyl, 3-pyrazinyl,2-pyridazinyl, 2-imidazolyl, 3-pyrazinyl, 2-pyridazinyl,1,2,3-triazole-1-yl, 1,2,4-triazol-3-yl, 3-quinolyl, 4-quinolyl,2-thiazolyl, 5-thiazolyl, 3-isoquinolyl, 4-isoquinolyl,2-benzimidazolyl, 2-indolyl and 3-indolyl, which may optionally bear oneor substituents independently selected from fluoro, chloro, bromo, iodo,hydroxy, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, allyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, formyl,acetyl, propionyl, butyryl and oxime derivaties of the last four groupsand O-methyl, ethyl, propyl, isopropyl and butyl ethers of said oximes,acetamido, propionamido, iso-propionamido, fluoromethyl, difluoromethyland trifluoromethyl.

Values of Ar of particular interest include for example, 2-pyridyl and3-pyridyl.

Specific values for Ar include, for example, 6-butoxypyrid-3-yl,3-pyridyl, 5-bromopyrid-2-yl, 3-quinolyl, 2-quinolyl, 5-methylpyrid-2-yland 5-methoxycarbonylpyrid-2-yl.

In a particular embodiment, when R¹ is hydroxy and R² is hydrogen or R¹and R² are joined so that CR¹ --CR² is a double bond, X is selected from--CH₂ CH₂ --, --CH═CH--, --C≡C--, --CH₂ O--, --CH₂ NH-- and --CH₂ S(wherein the sulphur atom optionally bears one or two oxygen atoms); andAr is as herein before defined; and when R¹ and R² are both hydrogen Xis selected from --CH₂ CH₂ --, --CH═CH-- and --C≡C--; and Ar is ashereinbefore defined, provided that Ar is not an imidazolyl moiety.

In particular, R¹ is hydroxy and R² is hydrogen; or R¹ and R² are joinedtogether so that CR¹ --CR² is a double bond; X is selected from --CH₂CH₂ --, --CH═CH--, --C≡C--, --CH₂ O--, --OCH₂ --, --CH₂ NH--, --NHCH₂--, --CH₂ CO--, --COCH₂ --, --N═CH--, --CH═N--, --CH₂ S-- and SCH₂ --(wherein the sulphur atom in the latter two groups may optionally bearone or two oxygen atoms); or R¹ and R² are both hydrogen and X isselected from --CH₂ CH₂ --, --CH═CH--, --C≡C--, --NHCH₂ --, --CH₂ NH--,--N═CH--, --CH═N--, --CH₂ CO-- and --COCH₂ --; Ar is a heterocyclicmoiety containing up to three heteroatoms independently selected fromnitrogen, oxygen and sulphur; and wherein Ar may optionally beunsubstituted or may bear one or more substituents independentlyselected from halogeno, hydroxy, amino, nitro, cyano, carboxy,carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di- (1-6C)alkyl!amino, N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno-(1-6C)alkyl,(1-6C)alkanoylamino, ureido, N'-(1-6C)alkylureido, (1-6C)alkanoyl andoxime derivatives thereof and O-(1-6C)alkyl ethers of said derivatives;

provided that when R¹ is hydroxy, X is not selected from --OCH₂ --,--NHCH₂ -- and --SCH₂ -- (optionally bearing one or two oxygen atoms onsulphur).

In one embodiment of the present invention, R¹ and R² are both hydrogen;and Ar and X have any of the meanings defined above.

In a further embodiment of the present invention, R¹ is hydroxy; R² ishydrogen;

X is selected from --CH₂ CH₂ --, --CH═CH--, --C≡C--, --CH₂ O--, --CH₂NH--, --CH═N--, --CH₂ CO--, --COCH₂ -- and --CH₂ S-- (wherein thesulphur atom in the latter two groups may optionally bear one or twooxygen atoms); Ar is a heterocyclic moiety containing up to threeheteroatoms independently selected from nitrogen, oxygen and sulphur;and wherein Ar may optionally be unsubstituted or may bear one or moresubstituents independently selected from halogeno, hydroxy, amino,nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di- (1-6C)alkyl!amino,N-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno-(1-6C)alkyl, (1-6C)alkanoylamino, ureido,N'-(1-6C)alkylureido, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives.

Particular, preferred and specific values are the appropriate valuesmentioned above.

In a further embodiment of the present invention, R¹ and R² are joinedtogether so that CR¹ --CR² is a double bond, and Ar and X are as definedabove.

In a particular embodiment the present invention provides a compound offormula I, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is hydrogen or hydroxy; R² is hydrogen; or

R¹ and R² are joined together so that CR¹ --CR² is a double bond;

X is selected from --CH₂ CH₂ --, --CH═CH--, --C≡C--, --CH₂ NH-- and--NHCH₂ --.

Ar is a heterocyclic moiety containing one, two or three heteroatomsselected from nitrogen, oxygen and sulphur;

and wherein Ar may optionally be unsubstituted or may bear one or moresubstituents independently selected from halogeno, hydroxy, amino,nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di- (1-6C)alkyl!amino,N-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, ureido,N'-(1-6C)alkylureido, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives; provided that when R¹and R² are both hydrogen Ar is not an imidazolyl moiety.

Particular, preferred and specific values are the appropriate valuesmentioned above.

In a further embodiment of interest there is provided a compound offormula I, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is hydroxy; R² is hydrogen; X is selected from --CH₂ O--, --CH═CH--and --C≡C-- (especially --CH═CH-- and C≡C--);

Ar is a heteroaryl moiety containing one or two nitrogen atoms(especially pyridyl)

and wherein Ar may optionally be unsubstituted or may bear one or moresubstituents independently selected from halogeno, hydroxy, amino,nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C) alkylamino, di- (1-6C)alkyl!amino,N-(1-6C)alkylcarbamoyl, di-N,N- (1-6 C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, ureido,N'-(1-6C)alkylureido, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives.

Particular, preferred and specific values are the appropriate valuesmentioned above.

In a further embodiment of the present invention there is provided acompound of formula I, or a pharmaceutically-acceptable salt thereof,wherein R¹ is hydroxy; R² is hydrogen; X is --C≡C--; and Ar is aheterocyclic moiety containing one, two or three heteroatoms selectedfrom nitrogen, oxygen and sulphur which is optionally substituted byone, two or three substituents independently selected from halogeno,hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-(1-6C)alkyl!amino, N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl,(1-6C)alkanoylamino, ureido, N'-(1-6C)alkylureido, (1-6C)alkanoyl andoxime derivatives thereof and O-(1-6C)alkyl ethers of said oximederivatives.

Particular, preferred and specific values include the appropriate valuesmentioned above.

Further compounds (and their pharmaceutically-acceptable salts) ofparticular interest include those in which R¹ is hydroxy, R² ishydrogen, X is --C≡C--, and Ar is a quinoyl or pyridyl moiety(especially a pyridyl moiety) which may optionally be unsubstituted ormay bear one, two or three substituents selected from halogeno, hydroxy,nitro, (1-6C)alkyl, (2-6C)alkenyl, (1-6C)alkoxy, (1-6C)alkanoylamino,halogeno (1-6C)alkyl, (1-6C)alkoxycarbonyl, (1-6C)alkanoyl, oximederivatives thereof and O-(1-6C)alkyl ethers of said oximes.

Compounds of the invention which are of particular interest include thecompounds described in the accompanying Examples (and theirpharmaceutically-acceptable salts), and are hence provided as a furtherfeature of the present invention.

A suitable pharmaceutically-acceptable salt of the present inventioncomprises an acid-addition salt derived from an inorganic or organicacid which provides a pharmaceutically-acceptable anion. Thus, examplesof salts of the present invention include acid-addition salts withhydrochloric, hydrobromic, nitric, sulphuric, phosphoric,trifluoroacetic, citric, tartaric, succinic, maleic, fumaric or aceticacid. In addition, suitable pharmaceutically-acceptable salts includewhere the compound of formula I is sufficiently acidic, for examplewhere the compound of formula I bears an acidic substituent such ascarboxy! those formed with a base which affords a pharmaceuticallyacceptable cation. Suitable bases include an alkali metal salt (such asa sodium or potassium salt), an alkaline earth metal salt (such as acalcium or magnesium salt), an ammonium salt or a salt with an organicbase which affords a physiologically-acceptable cation such as a saltwith methylamine, dimethylamine, triethylamine, piperidine ormorpholine.

The compounds of the present invention may be obtained by standardprocedures of organic chemistry already known to be applicable to thepreparation of structurally analogous compounds. Such procedures for thepreparation of the compounds of formula I, or pharmaceuticallyacceptable salts thereof, are provided as a further feature of thepresent invention and are illustrated by the following preferredprocesses in which the various generic radicals, for example, R¹, R², XAr may take any of the meanings hereinbefore defined.

Thus, according to the present invention there is also provided aprocess for preparing a compound of formula I, or apharmaceutically-acceptable salt thereof, which process comprises:

(a) For those compounds of formula I in which R¹ and R² are bothhydrogen, reducing a compound of formula I in which R¹ and R² are joinedtogether so that CR¹ --CR² is a double bond (provided that X is not--CH═CH-- or --C≡C--).

The reduction may be carried out, for example, by catalytichydrogenation, or by reaction with a suitable reducing agent. Suitablereaction conditions include, for example, catalytic hydrogenation usinga catalyst which comprises a noble metal. Particular catalysts includepalladium, platinum and nickel (especially when in the finely dividedstate known as raney nickel), and catalysts in which the noble metal issupported on an inert carrier such as carbon. A specific example of asupported catalyst is Pd/C. The reduction is conveniently carried out ina solvent of, for example, an alcohol (such as ethanol), and at (ornear) ambient temperature and optionally under pressure.

Further suitable reaction conditions include, for example, reductionwith a borane such as diborane. The reaction is generally carried out inan inert solvent of, for example, tetrahydrofuran or methyl t-butylether at, for example, 0°-60° C. It may be preferable to cool thereaction below ambient temperature (eg. to about 0° C.) during thereduction. The borane generated may be hydrolysed by treatment with anorganic acid such as acetic acid, which hydrolysis may be carried out at0°-60° C., and may be accelerated by heating (eg. refluxing).

(b) For compounds of formula I in which R¹ and R² are joined together sothat CR¹ --CR² is a double bond, dehydrating a compound of formula I inwhich R¹ is hydroxy and R² is hydrogen.

The dehydration may be carried out using an acid such as sulphuric acid(eg. concentrated sulphuric acid), or p-toluene sulphonic acid. Thereaction is conveniently carried out with heating, and conveniently aninert solvent is employed. For example, the reaction may be carried outusing sulphuric acid at temperatures of about 70°-130° C.; or usingp-toluene sulphonic acid in a hydrocarbon solvent of, for example,toluene or xylene at ambient temperature to reflux, and preferably atreflux. The dehydration may also be carried out using trifluoroaceticacid in an inert solvent such as dichloromethane (at ambient temperatureto reflux temperature).

(c) For compounds of formula I in which R¹ and R² are joined together sothat CR¹ --CR² is a double bond, treating a compound of formula II inwhich Z is a leaving group with a base.

Suitable values for Z include, for example, halogen such as chloro,bromo, iodo, or a methylsulphonyloxy or toluenesulphonyloxy group.Suitable bases include hydroxide (such as potassium or sodiumhydroxide), and alkoxide (such as potassium t-butoxide or sodiumethoxide).

The reaction is conveniently carried out in the presence of a solvent,preferably a polar organic solvent. Suitable solvents include, forexample, an alcohol (such as ethanol), or an aprotic solvent such asdimethylformamide or N-methylpyrrolidone. The reaction may be carriedout at ambient temperature or at an elevated temperature, such as at atemperature between ambient and the reflux temperature of the reactionmixture. This method is generally preferred over that described in (b)when X is --OCH₂ -- or --SCH₂ --.

The compounds of formula II may be prepared from a compound of formula Iin which R¹ is hydroxy. For example, where Z is halogen the compound offormula I in which R¹ is hydroxy and R² is hydrogen may be reacted withthe appropriate phosphorous halide (eg. PCl₅, PBr₃ or PI₃), or where Zis chloro, by reaction with thionyl chloride. The compound of formula Iin which R¹ is hydroxy may be reacted with mesyl chloride to thecompound in which Z is methylsulphonyloxy; and with tosyl chloride togive Z is toluene sulphonyloxy.

(d) For those compounds of formula I in which X is --CH₂ CO--, reactingan organometallic compound of formula Ar--M in which M is a metal atomor a derivative thereof, with a compound of formula III.

Suitable values for M include, for example, magnesium and lithium. Inthe case where M is magnesium it is conveniently present in the form ofa derivative of formula --MgX where X is a halogen atom such as iodo orbromo, so that the organometallic compound has the formula Ar--MgX andis in the form known as a Grignard Reagent. The reaction is generallycarried out in an inert solvent such as dry diethyl ether ortetrahydrofuran. For example, the reaction may be carried out at atemperature between 0° C. and the reflux temperature of the reactionmixture.

The compounds of formula Ar--M may be prepared from the correspondingcompound of formula Ar--"hal" in which "hal" is a halogen atom, such asiodo or bromo as is well known in the art.

e) For those compounds of formula I in which X is --CH₂ --NH-- or--NHCH₂ --, reducing a compound of formula I in which X is --CH═N-- or--N═CH-- (as appropriate).

The reaction may be carried out using a chemical reducing agent such asa hydride in a solvent such as an alcohol at ambient temperature. Thus,in a particular example, the reduction may be carried out using sodiumborohydride in a solvent of methanol at ambient temperature. Thereduction may also be carried out by selective catalytic hydrogenationusing similar conditions to those described under (a) above.

It will be appreciated that the preferred method of reduction willdepend upon the value of X. Thus, for example, where debenzylation ispossible (eg. when X is --NHCH₂ --), it is generally preferred that achemical reducing agent is employed.

The compounds of formula I in which X is --CH═N-- may be prepared byreaction of a compound of formula IV with a compound of formula Ar--NH₂.The reaction is generally carried out in an inert hydrocarbon solventsuch as toluene or benzene, with heating (eg. at reflux) and thereaction may be accelerated by removing water generated in the reactionby azeotropic distillation. Similarly, the compounds of formula I inwhich X is --N═CH-- may be prepared by reaction of a compound of formulaAr--CHO with a compound of formula V.

f) For those compounds of formula I in which X is --CH₂ NH--, --CH₂ O--,--CH₂ S--, R¹ is hydroxy and R² is hydrogen, reacting a compound offormula Ar--Z in which Z is --NH₂, --OH or SH as appropriate with acompound of formula VI.

The reaction is conveniently carried out in a solvent such an inerthydrocarbon eg. toluene with heating. The reaction may be facilitated bythe presence of acid or base.

The compound of formula VI is conveniently generated in situ, by, forexample, treating quinuclidin-3-one with trimethylsulphoxonium iodide inthe presence of a base of, for example, an alkali metal hydride such assodium hydride and in a solvent such as dimethylformamide, or an alkalimetal hydroxide such as sodium hydroxide in a solvent such as an aqueoussolvent.

The compound of formula VI may also be prepared from a "halohydrin" asis well known in the art. The halohydrin may be prepared, for example,by addition of HOCl to the corresponding olefin and the halohydrintreated with base (eg. NaOH) to give the compound of formula VI.

g) For compounds of formula I in which X is --CH═CH--, reacting acompound of formula Ar--CH2--P⁺ Ph₃ W⁻ with a compound of formula IV inthe presence of a base.

Suitable bases include alkoxides, such as potassium t-butoxide, and thereaction is conveniently carried out in an inert solvent such astetrahydrofuran with cooling below ambient temperature eg -40° C. to 0°C.); and metal hydrides such as sodium hydride in a solvent such asdimthyl formamide or dimethylsuphoxide. A particularly suitable base is,for example, sodium dimsyl which may conveniently be used in a solventsuch as dimethyl suphoxide.

The compounds of formula Ar--CH2--P⁺ Ph₃ W⁻ may be prepared by reactionof a compound of formula ArCH₂ --hal in which "hal" is halogen, such aschloro, with triphenylphosphine as is well known in the art.

h) For those compounds of formula I in which X is --CH₂ CH₂ --, reducinga compound of formula I in which X is --CH═CH-- or in which X is--C≡C--.

The reaction may conveniently be carried out by catalytic hydrogenationusing conditions similar to those mentioned in (a) above.

In an alternative synthesis a compound of formula ArCH₂ CH₂ --halwherein "hal" represents a halogen atom such as bromo, is reacted withquinuclidin-3-one in the presence of sec-butyl lithium, with cooling (eg-70° C.) in an inert solvent such as tetrahydrofuran.

i) For compounds of formula I in which X is --COCH₂ --, reacting acompound of formula Ar--CH₂ M in which M is a metal atom or a derivativethereof, with a compound of formula VII.

Suitable values for M and suitable reaction conditions are thosementioned in (d) above. The compounds of formula Ar--CH₂ M may beprepared from the corresponding halogeno compound in a manner analogousto the preparation of compounds of formula Ar--M discussed in (d) above.

j) For those compounds of formula I in which X is --CH₂ O-- or --CH₂S--, reacting a compound of formula ArCH2Z¹ with a compound of formulaVIII, in which Z¹ is a leaving group and Z² is --YM, or Z¹ is --YM andZ² is a leaving group, and wherein Y is oxygen or sulphur (asappropriate) and M is a metal atom.

Suitable leaving groups include, for example, halogen (such as chloro,bromo or iodo), methanesulphonyloxy, toluenesulphonyloxy ortrifluoromethanesulphonyloxy;.and suitable metals include, for examplesodium and lithium.

The process is generally performed in the presence of a suitablesolvent, for example, a hydrocarbon, such as toluene or xylene, or anether such as dioxan or tetrahydrofuran, and at a temperature in therange, for example 20°-150° C.

It may be desirable to protect the quinuclidine nitrogen atom during thereaction, especially when Z¹ is --YM, as described in (1) below. It maybe desirable to protect R¹ when it represents a hydroxy group as, forexample, a silyl ether.

k) For those compounds of formula I in which X is --OCH₂ -- or --SCH₂ --and R¹ and R² are both hydrogen, reacting a compound of formula ArYH inwhich Y is oxygen or sulphur as appropriate with a compound of formulaIX in which Z is a leaving group.

Suitable leaving groups include halogen, such as chloro, bromo or iodo,methanesulphonyloxy and toluenesulphonyloxy. The reaction is generallycarried out in the presence of a base such as an alkali metal hydroxide,eg sodium or potassium hydroxide, and in a solvent such asdimethylsulphoxide or dimethylformamide.

l) For compounds of formula I in which X is --OCH₂ --, --SCH₂ --,--CH2O--, or --CH₂ S--, deprotecting a compound of formula X in which Qis a protecting group.

Suitable values for Q include, for example, --BH₃ or an oxygen atom.When Q is --BH₃ the deprotection may be carried out by treatment with anacid such as hydrochloric acid in a solvent such as acetone. Q is anoxygen atom deprotection may be carried out by reduction using asuitable reducing agent such as sulphur dioxide.

The compounds of formula X in which X is --CH₂ O-- or --CH₂ S-- may beprepared by methods analogous to those described in (j), and in which Xis --OCH₂ -- or --SCH₂ -- by methods analogous to those described in (k)above, but in which the starting material containing the quinuclidinemoiety is protected by Q. A preferred way of preparing compounds offormula X in which X is --CH₂ O-- or --CH₂ S-- and R¹ is hydroxy and R²is hydrogen is by a procedure analogous to that described in (f) inwhich the compound of formula X is protected by Q. The quinuclidinemoiety in the various starting materials may be protected usingmethodology well known in the art. Thus, for example, those in which Qis BH₃ may be prepared by reaction of the appropriate quinuclidinemoiety with BH₃.THF, generally with cooling (for example at -70° C.);whilst those in which Q is an oxygen atom may be prepared by oxidationof the appropriate quinuclidine moiety with, for example, 30% hydrogenperoxide.

m) For those compounds of formula I in which X is --C≡C--, reacting acompound of formula I in which X is --CH═CH-- with a halogen, followedby treatment with a base.

A suitable halogen is bromine and the reaction is conveniently carriedout in an inert solvent such as carbon tetrachloride. Suitable basesinclude, for example, potasium t-butoxide. This treatment isconveniently carried out in a solvent such as THF, with heating (eg. ata temperature between ambient and about 70° C.).

n) For those compounds of formula I in which R¹ is hydroxy, R² ishydrogen and X is --C≡C--, reacting a compound of formula Ar--C≡C--M inwhich M is a metal atom, with quinuclidin-3-one.

A suitable metal is lithium and suitable reaction conditions includethose mentioned in (d) above.

o) For those compounds in which R¹ and R² are hydrogen and X is --C≡C--,reacting a compound of formula Ar--C≡C--M in which M is a metal atomwith a compound of formula VIII in which Z is a leaving group.

Suitable values for Z include, for example, halogen (such as chloro,bromo or iodo), methanesulphonyloxy, toluenesulphonyloxy ortrifluoromethanesulphonyloxy; suitable values for M include, forexample, lithium; and suitable reaction conditions include thosementioned under (d) above.

p) For those compounds in which X is --C≡C--, and R¹ is hydrogen orhydroxy and R² is hydrogen, reacting a compound of formula XI with acompound of formula Ar--Z in which Z is a leaving group in the presenceof a catalyst.

Suitable catalysts include, for example, transition metal complexes suchas palladium or nickel complexes. Particular catalysts are palladium(II) complexes, a specific example of which is Pd(PPh₃)₂ Cl₂. Suitablevalues for Z include, for example, halogen (such as chloro, bromo oriodo), methanesulphonyloxy, toluenesulphonyloxy andtrifluoromethanesulphonyloxy. The reaction is generally carried out inthe presence of a base, for example, an amine such as triethylamine andin a solvent such as dimethylformamide with heating (for example at 60°to 100° C.). The reaction is preferably carried out in the prersence ofcopper(I)iodide. Compounds of formula XX may be prepared according toScheme 1a and 2b.

q) For those compounds in which X is --C═C-- and R¹ is hydrogen orhydroxy and R² is hydrogen, reacting a compound of formula XII with acompound of formula Ar--Z in which Z is a leaving group in the presenceof a catalyst.

Suitable reaction conditions are those mentioned under (p) above.Compounds of formula XII may be prepared according to Scheme 1b and 2a.

r) For those compounds of formula I in which X is --CH₂ CH₂ -- or--CH═CH--, reducing a compound of formula I in which X is --C═C--.

The reaction may conveniently be carried out by catalytic hydrogenationusing conditions similar to those mentioned in (a) above.

When a compound of formula I is desired in which X is --CH═CH--, aselective catalyst is preferably employed such as palladium which hasbeen deposited on barium sulphate and then treated with quinoline("Lindlars catalyst").

s) For those compounds of formula I in which X is --SCH₂ -- or --CH₂ S--wherein the sulphur atom bears one or two oxygen atoms, oxidising thecorresponding compound of formula I in which X is --SCH₂ -- or --CH₂S--.

The compounds of formula I in which X is --SCH₂ -- may be be oxidised tothese in which the sulphur atom bears an oxygen atom (that is to a"sulphoxide") using, for example an appropriate quantity of sodiumperiodate. Further oxidation to the compound in which the sulphur atombears two oxygen atoms (that is a "sulphone") may be carried out using aperacid such as peracetic acid or hydrogen peroxide. The oxidation ofsulphur compounds to the corresponding sulphoxides and sulphones is wellknown in the chemical art. Compounds of formula I in which X is --CH₂S-- may be oxidised to the corresponding sulphoxides or sulphones in thesame way.

In some cases oxidation of compounds of formula I to give a sulphone maybe accompanied by some oxidation of the nitrogen atom in thequinuclidine ring to the N-oxide. In such cases the quinuclidine N-oxidemoiety may be reduced back to a quinuclidine moiety without affectingthe sulphone using reducing agents well known in the art, such assulphur dioxide.

It will be appreciated that in some of the reactions mentioned herein itmay be necessary/desirable to protect any sensitive groups in thecompounds. The instances where protection is necessary or desirable andsuitable methods for protection are known to those skilled in the art.Thus, if reactants include groups such as amino, carboxy or hydroxy itmay be desirable to protect the group in some of the reactions mentionedherein. Suitable protecting groups for hydroxy include, for example,silyl groups such as trimethylsilyl or t-butyldimethylsilyl,tetrahydropyranyl and esterifing groups such as a methyl or ethyl ester;and for amino groups include benzyloxycarbonyl and t-butoxycarbonyl.Carboxy groups may be protected in a reduced form such as in the form ofthe corresponding protected alcohol, which may be subsequently oxidisedto give the carboxy group. The protecting groups may be removed at anyconvenient stage in the synthesis using conventional techniques wellknown in the chemical art.

It will also be appreciated that the preferred process for preparing aparticular compound of formula I will depend upon the nature of thevarious radicals. Similarly, the preferred choice of reagent will dependupon the nature of the various radicals present. For example, when it isrequired to reduce a particular compound the reducing agent willgenerally be selected to be one which does not interfere with othergroupings present.

It will also be appreciated that certain of the various optionalsubstituents in the compounds of the present invention may be introducedby standard aromatic substitution reactions or generated by conventionalfunctional group modifications either prior to or immediately followingthe processes mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of, substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acylhalide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogeno group. Particularexamples of modifications include the reduction of a nitro group to anamino group by for example, catalytic hydrogenation with a nickelcatalyst or treatment with iron in the presence of hydrochloric acidwith heating; oxidation of alkylthio to alkylsulphinyl oralkylsulphonyl.

When a pharmaceutically-acceptable salt of a compound of the formula Iis required, it may be obtained, for example, by reaction of saidcompound with the appropriate acid (which affords a physiologicallyacceptable anion), or with the appropriate base (which affords aphysiologically acceptable cation), or by any other conventional saltformation procedure.

As mentioned previously, the compounds of the formula I (and theirpharmaceutically-acceptable salts) are inhibitors of the enzyme squalenesynthase. Thus the compounds of the present invention are capable ofinhibiting cholesterol biosynthesis by inhibition of de novo squaleneproduction.

The beneficial pharmacological properties of the compounds of thepresent invention may be demonstrated using one or more of the followingtechniques.

(a) Inhibition of Squalene synthase

In this test, the ability of a compound to prevent the formation ofsqualene from a radioactive substrate (tritiated farnesyl pyrophosphate)is assessed.

The test compound is incubated at a concentration of 25 micromolar in200 μl of a buffered solution containing potassium phosphate (50 mM),MgCl₂ (4.95 mM), KF (9.9 mM), NADPH (0.9 mM) and rat liver microsomalprotein (20 μg). Rat liver microsomes are prepared by the methoddescribed in published European Patent Application No. 324,421 andstored in liquid nitrogen prior to assay. Assay vials are kept at 37° C.throughout the incubation.

The reaction is started with the addition of the substrate (1- ³H!-farnesyl pyrophosphate), final concentration 20 μM, and stopped after15 minutes reaction time with the addition of 50 μl of 4% KOH. Thereaction products are separated from unreacted substrate afterapplication to a C-18 octadecyl 1 ccBond column (Analytichem Int productNo. 617101). An aqueous fraction is eluted with 250 μl of 0.1M KOH.Squalene is then eluted with 1.0 ml 10% ethylacetate in hexane andradioactivity determined. The difference in radioactivity in thepresence and absence of the test compound is used to determine the levelof inhibition. If the test compound inhibits at greater than about 70%at 25 micromolar, it is generally re-tested at 25 and 2.5 micromolar.The IC₅₀ (concentration which results in a 50% inhibition of squaleneproduction), of the test compound can be determined by testing thecompound at several, for example five, concentrations predicted from thetwo concentration results. The IC₅₀ can then be determined from a plotof percentage inhibition against concentration of test compound.

In general, compounds of formula I show significant inhibition in theabove test at a concentration in the range of about 0.001 to 25 μM.

By way of illustration of the squalene synthase inhibitory properties ofthe compounds of formula I, the compound of formula I described inExample 1 below gave about 99% inhibition at 2.5 μM.

(b) Acute rat cholesterol synthesis assay.

This is an acute in vivo test in the rat to measure de novo hepaticcholesterol synthesis from exogenously administered ¹⁴ C-acetate.

Female rats (35-55 g) are housed in reverse lighting conditions (redlight from 0200 h-1400 h) for a period of about 2 weeks prior to test.Animals are allowed free access to chow and drinking water throughoutthis period. At test, animals should weigh 125-150 g.

Test compounds may be administered by oral gavage, dissolved orsuspended in 0.5% polysorbate, or by ip or iv dosing. Control animalsreceive vehicle alone. After 1 hour the rats are injected ip with 25 μCi2-¹⁴ C!-acetate (NEN DUPONT. specific activity, 45-60 mCi/mmol NEC-085H,or AMERSHAM specific activity, 50-60 mCi/mmol CFA 14) in a volume of0.25 ml saline (100 μCi/ml). After a further hour, rats are terminallyanaesthetised with halothane and a blood sample obtained from theabdominal vena cava.

1 ml of plasma is lyophilised and then saponified in 2 ml ethanolic KOH(1 part 33% KOH, 9 parts ethanol) at 75° C. for 2 hours. After additionof an equal quantity of water, non-saponifiable lipids are extractedwith two 5 ml volumes of hexane. The hexane extracts are evaporated todryness and the residues dissolved in ethanol to determine cholesterolspecific radioactivity. ED₅₀ values can be determined in the standardway.

In general, compounds of formula I show activity in the range of about0.1 to 100 mg/kg.

By way of illustration, the compound of formula I described in Example 1gave a 71% decrease in the rate of cholesterol biosynthesis.

In an alternative in vivo test, de novo hepatic cholesterol synthesisfrom exogenously administered ³ H-mevalonolactone is measured. The aboveprocedure is used but with ³ H-mevalonolactone (2.5 μCi) administered inplace of ¹⁴ C-acetate and the test compound is generally administered asa solution or suspension in 10% dimethylsulphoxide in 0.5%hydroxypropylmethylcellulose.

No overt toxicity was detected when compounds of the formula I wereadministered at several multiples of their minimum inhibitory dose orconcentration.

When used in the treatment of diseases and medical conditions in whichan inhibition of cholesterol biosynthesis is desired, for example in thetreatment of hypercholesterolemia or atherosclerosis, it is envisagedthat a compound of formula I (or a pharmaceutically acceptable saltthereof) will be administered orally, intravenously, or by some othermedically acceptable route so that a dose in the general range of, forexample, 0.01 to 50 mg per kg body weight is received. However it willbe understood that the precise dose administered will necessarily varyaccording to the nature and severity of the disease, the age and sex ofthe patient being treated and the route of administration.

In general, the compounds of formula I (or a pharmaceutically-acceptablesalt thereof) will usually be administered in the form of apharmaceutical composition, that is together with a pharmaceuticallyacceptable diluent or carrier, and such a composition is provided as afurther feature of the present invention.

A pharmaceutical composition of the present invention may be in avariety of dosage forms. For example, it may be in the form of tablets,capsules, solutions or suspensions for oral administration, in the formof a suppository for rectal administration; in the form of a sterilesolution or suspension for parenteral administration such as byintravenous or intramuscular injection.

A composition may be obtained by conventional procedures usingpharmaceutically acceptable diluents and carriers well known in the art.Tablets and capsules for oral administration may conveniently be formedwith a coating, such as an enteric coating (for example, one based oncellulose acetate phthalate), to minimise dissolution of the activeingredient of formula I (or a pharmaceutically-acceptable salt thereof)in the stomach or to mask unpleasant taste.

As mentioned above, the compounds of the present invention are squalenesynthase inhibitors and hence possess the property of inhibitingcholesterol biosynthesis. Thus the compounds of the present inventionwill be useful in treating diseases or medical conditions in which aninhibition of squalene synthase is desirable, for example those in whicha lowering of the level of cholesterol is blood plasma is desirable. Inparticular, the compounds of the present invention will be useful intreating hypercholesterolemia and/or ischaemic diseases associated withatheromatous vascular degeneration such as atherosclerosis. Thecompounds of the present invention will also be useful in treatingfungal infections.

According to a further feature of the present invention there isprovided a method of inhibiting squalene synthase in a warm-bloodedanimals (such as man) requiring such treatment, which method comprisesadministering to said animal an effective amount of a compound offormula I or a pharmaceutically-acceptable salt thereof wherein:

R¹ is hydrogen or hydroxy;

R² is hydrogen; or

R¹ and R² are joined together so that CR¹ --CR² is a double bond;

X is selected from --CH₂ CH₂ --, --CH═CH--, --C≡C--, --CH₂ O--, --OCH₂--, --CH₂ NH--, --CH═N--, --N═CH--, --NHCH₂ --, --CH₂ CO--, --COCH₂ --,--CH₂ S-- and --SCH₂ -- (wherein the sulphur atom in the latter twogroups may optionally bear one or two oxygen atoms);

Ar is a heterocyclic moiety containing up to three heteroatomsindependently selected from nitrogen, oxygen and sulphur;

and wherein of Ar may optionally be unsubstituted or may bear one ormore substituents independently selected from halogeno, hydroxy, amino,nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C) alkoxy, (1-6C) alkylamino, di- (1-6C)alkyl!amino,N-(1-6C) alkylcarbamoyl, di-N, N- (1-6C)alkyl!carbamoyl, (1-6C )alkoxycarbonyl, (1-6C) alkylthio, (1-6C) alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno-(1-6C)alkyl, (1-6C)alkanoylamino,(1-6C)alkanoyl and oxime derivatives thereof and O-(1-6C)alkyl ethers ofsaid oxime derivatives;

provided that when R¹ is hydroxy, X is not selected from --OCH₂ --,--NHCH₂ --, --N═CH--, and --SCH₂ --.

Particular, preferred and specific values include those mentioned above.

In particular, the present invention provides a method of inhibitingcholesterol biosynthesis, and more particularly to a method of treatinghypercholesterolemia and atheromatous vascular degeneration (such asatherosclerosis).

Thus the present invention also provides the use of a compound offormula I (as herein defined), or a pharmaceutically-acceptable saltthereof, for the manufacture of a medicament for treating diseases ormedical conditions in which a lowering of the level of cholesterol inblood plasma is desirable (such as hypercholesterolemia andatherosclerosis).

The compounds of the present invention may, if desired, be administeredtogether with (or sequentially to) one or more other pharmacologicalagents known to be useful in the treatment of cardiovascular disease,for example, together with agents such as HMG-CoA reductase inhibitors,bile acid sequestrants, other hypocholesterolaemic agents such asfibrates, for example gemfibrozil, and drugs for the treatment ofcoronary heart disease. As a further example, the compounds of thepresent invention may, if desired, be administered together with (orsequentially to) an angiotensin converting enzyme (ACE) inhibitor, suchas captopril, lisinopril, zofenopril or enalapril.

Compounds which inhibit squalene synthase have also found utility asantifungal agents. Thus the present invnetion also provides a method oftreating fungal infections comprising adimistering a compound of formulaI, or a non-toxic salt thereof, to an organism in need of suchtreatment.

In particular, the present invention-also provides a method of treatingfungal infections which comprises administration to an a warm bloodedanimal, such as man, in need of such treatment an effective amount of acompound of formula I, or a pharmaceutically acceptable salt thereof.

When used as anti-fungal agents the compounds may be formulated in avariety of ways, the nature of such formulation depending on whether theuse is for controlling pathogens infecting mammals such as man, or inagriculture such as in soil or plants, or some other object. For medicalapplications, the compounds of the present invention may, in addition tothe formulations mentioned above, be adapted for topical administrationand such a composition is provided as a further feature of the presentinvention. Such compositions may be in a variety of forms, for examplecreams or lotions.

The invention will now be illustrated by the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo;

(ii) operations were carried out at room temperature, that is in therange 18°-26° C.;

(iii flash column chromatography or medium pressure liquidchromatography (MPLC) was performed on silica gel (Merck KieselgelArt.9385, obtained from E Merck, Darmstadt, Germany);

(iv) yields are given for illustration only and are not necessariliy themaximum attainable by diligent process development;

(v) proton NMR spectra were normally determined at 200 MHz usingtetramethylsilane (TMS) as an internal standard, and are expressed aschemical shifts (delta values) in parts per million relative to TMSusing conventional abbreviations for designation of major peaks: s,singlet, m, multiplet; t, triplet; br, broad; d, doublet;

(vi) all end-products were characterised by microanalysis, NMR and/ormass spectroscopy; and

(vii) conventional abbreviations are used for individual radicals andrecrystallisation solvents, for example, Me=methyl, Et=ethyl, Pr=Propyl,Pr^(i) =isopropyl, Bu=butyl, Bu^(i) =isobutyl, Ph=phenyl; EtOAc=ethylacetate, Et₂ O=ether, MeCN=acetonitrile, MeOH=methanol, EtOH=ethanol,Pr^(i) OH=2-propanol, H₂ O=water.

EXAMPLE 1

A stirred mixture of 3-ethynyl-3-hydroxyquinuclidine (600 mg),5-bromo-2-n-butoxypyridine (920 mg), bis-(triphenylphosphine)-palladium(II) chloride (140 mg), copper (I) iodide (70 mg) and dry triethylamine(10 ml) in dry dimethylformamide (20 ml) was heated at 90° C. under anatmosphere of argon for 6 hours. The reaction mixture was cooled and thedimethylformamide and triethylamine were removed by evaporation. Theresidue was treated with 2M aqueous sodium hydroxide solution (20 ml)and the resulting mixture extracted with dichloromethane (3×20 ml). Theorganic extracts were combined, dried (MgSO₄) and evaporated to give abrown residue which was crystallised from acetonitrile to yield 3-2-(6-butoxy-3-pyridyl)ethynyl!quinuclidin-3-ol (300 mg) as a solid, m.p.149°-151° C.; microanalysis, found: C, 71.3; H, 7.9; N, 8.9%; C₁₈ H₂₄ N₂O₂ 0.1H ₂ O requires: C, 71.47; H, 8.08; N, 9.26%; NMR (DHSOd₆):0.9-1.0(3H, t), 1.2-1.35(1H, m), 1.35-1.5(2H, m), 1.5-1.65(1H, m),1.65-1.75(2H, m), 1.75-2.0(3H, m), 2.6-2.75(4H, t), 2.8-2.85(1H, d),3.02-3.17(1H, d), 4.2-4.3(2H, t), 5.55(1H, s), 6.75-6.83(1H, d),7.65-7.72(1H, d) and 8.2(1H, s); m/Z 301 (M+H).

The 5-bromo-2-n-butoxypyridine used as a starting material was preparedas follows:

Sodium hydride (60% w/v dispersion in mineral oil; 1.8 g) was added inportions over 20 minutes to n-butanol (100 ml) with stirring. Themixture was then stirred until no further hydrogen evolution was noted.2,5-Dibromopyridine (7.1 g) was added and the resulting mixture stirredat reflux for 6 hours. After cooling, the n-butanal was removed byevaporation and the residue was treated with water (50 ml) and extractedwith dichloromethane (2×20 ml). The organic extracts were combined,washed with water (20 ml), dried (MgSO4) and evaporated to give5-bromo-2-n-butoxypyridine (6.3) as a pale yellow oil, NMR (DHSOd₆):0.9-0.96(3H, t), 1.32-1.5(2H, m), 1.62-1.76(2H, m), 4.2-4.28(2H, t),6.79-6.82(1H, d), 7.85-7.9(1H, d of d) and 8.26(1H, d).

The 3-ethynyl-3-hydroxyquinuclidine used as starting material wasobtained as follows:

A solution of n-butyl lithium (100 ml of a 2M solution in pentane) wasadded portion-wise over a period of 20 minutes to a stirred solution ofethynyltrimethylsilane (19.6 g) in dry tetrahydrofuran (400 ml) at -70°C. The mixture was stirred for 1 hour at -70° C. A solution ofquinuclidin-3-one (2.4 g) in dry tetrahydrofuran (100 ml) was then addedto the mixture and the mixture stirred for 1 hour at -70° C. Methanol (1ml) was then added to the mixture and the mixture allowed to warm toroom temperature. The solvents were removed by evaporation. Methanol(500 ml) and potassium carbonate (40 g) were added to the residue andthe mixture was stirred for 1 hour. The solvent was removed byevaporation. The residue was triturated under water (500 ml) and thesolid obtained dried in vacuo. There was thus obtained3-ethynyl-3-hydroxy-quinuclidine as a solid, m.p. 193°-197° C.; NMR(DMSO-d₆): 1.5-1.3(1H, m), 1.4-1.6(1H, m), 1.7-1.95(3H, m), 2.55-2.8(5H,m), 2.95(1H, d), 3.3(1H, d) and 5.4(1H, s); m/Z 152 (M+H).

EXAMPLE 2

The procedure described in Example 1 was repeated using 3-bromopyridinein place of 5-bromo-2-n-butoxypyridine. Purification by flashchromatography on silica gel using 10% methanol in dichloromethanecontaining 1% ammonia (density, 0.88 g/cm³) as eluent, followed byrecrystallisation from a mixture of propan-2-ol and diethyl ether, gave3- 2-(3-pyridyl)ethynyl!quinuclidin-3-ol which was treated with etherealhydrogen chloride to give 3- 2-(3-pyridyl)ethynyl!quinuclidin-3-olhydrochloride, NMR(DMSOd₆): 1.7-1.85(1H,m), 1.87-2.05(1H,m),2.05-2.26(2H,m), 2.3(1H,br), 3.05-3.39(3H,m), 3.65(1H,d), 5.1(1H,br+HO),7.65(2H,m), 8.12(1H,br), 8.65(1H,br), 8.85(1H,br) and 10.6(1H,br).

EXAMPLE 3

The procedure described in Example 1 was repeated using2,5-dibromopyridine in place of 5-bromo-2-n-butoxypyridine. Purificationby flash chromatography on silica gel using 10% methanol indichloromethane containing 1% ammonia (density, 0.88 g/cm³) as eluent,gave 3- 2-(5-bromopyrid-2-yl)ethynyl!quinuclidin-3-ol as a solid, m.p.194°-198° C.; NMR(DHSOd₆): 1.25-1.42(1H,m), 1.55-1.72(1H,m),1.80-2.0(2H,m), 2.02(1H,br), 2.75(4H,t), 2.9(1H,d), 3.16(1H,d),5.18(1H,s), 7.45(1H,d), 8.05(1H,d of d) and 8.67(1H,d).

EXAMPLE 4

The procedure described in Example 1 was repeated using 3-bromoquinolinein place of 5-bromo-2-n-butoxypyridine to give, after crystallisationfrom a mixture of dichloromethane and n-hexane, 3-2-(3-quinolyl)ethynyl!quinuclidin-3-ol as a solid, m.p. 194°-198° C.;NMR (DMSOd₆, 100° C.): 1.25-1.42(1H,m), 1.55-1.72(1H,m), 1.8-2.0(2H,m),2.02(1H,br), 2.75(4H,t), 2.9(1H,d), 3.16(1H,d), 5.65(1H,s),7.43-7.55(1H,m), 7.6-7.7(1H,m), 7.82-7.92(2H,m), 8.35(1H,d) and8.72(1H,s).

EXAMPLE 5

The procedure described in Example 1 was repeated using 2-iodoquinolinein place of 5-bromo-2-n-butoxypyridine. Purification by flashchromatography on silica gel using 10% methanol in dichloromethanecontaining 1% ammonia (density, 0.88 g/cm³) as eluent gave 3-2-(2-quinolyl)ethynyl!quinuclidin-3-ol; NMR(DHSOd₆): 1.25-1.42(1H,m),1.55-1.72(1H,m), 1.8-2.0(2H,m), 2.02(1H,br), 2.75(4H,t), 2.9(1H,d),3.16(1H,d), 5.8(1H,s), 7.5-7.7(2H,m), 7.77-7.85(1H,m), 8.0(2H, d) and8.4(1H,d).

EXAMPLE 6

The procedure described in Example 1 was repeated using2-bromo-5-methylpyridine in place of 5-bromo-2-n-butoxypyridine.Purification by flash chromatography on silica gel using 10% methanol indichloromethane containing 1% ammonia (density, 0.88 g/cm³) as eluentgave 3- 2-(5-methylpyrid-2-yl)ethynyl!quinuclidin-3-ol as a solid, m.p.176°-180° C.; NMR(DMSOd₆): 1.25-1.42(1H,m), 1.55-1.72(1H,m),1.8-2.0(2H,m), 2.02(1H,br), 2.35(3H,s), 2.75(4H,t), 2.9(1H,d),3.16(1H,d), 5.8(1H,s), 7.37(1H,d), 7.6(1H,d) and 8.4(1H,br).

EXAMPLE 7

The procedure described in Example 1 was repeated using2-chloro-5-(methoxycarbonyl)pyridine in place of5-bromo-2-n-butoxypyridine. Purification by flash chromatography onalumina (ICN Biomedicals N32-63) using 2% methanol in dichloromethane aseluent gave 3- 2-(5-methoxycarbonylpyrid-2-yl)ethynyl!quinuclidin-3-olas a solid, m.p. 180°-182° C., NMR(DMSOd₆): 1.25-1.42(1H,m),1.55-1.72(1H,m), 1.8-2.0(2H,m), 2.02(1H,br), 2.75(4H,t), 2.9(1H,d),3.16(1H,d), 3.92(3H,s), 5.8(1H,s), 7.52(1H,d), 8.28(1H,d of d) and9.01(1H,d).

EXAMPLE 8

Illustrative pharmaceutical dosage forms suitable for presenting thecompounds of the invention for therapeutic or prophylactic use includethe following tablet and capsule formulations, which may be obtained byconventional procedures well known in the art of pharmacy and aresuitable for therapeutic or prophylactic use in humans:

    ______________________________________                                        (a) Tablet I            mg/tablet                                             Compound Z*             1.0                                                   Lactose Ph. Eur.        93.25                                                 Croscarmellose sodium   4.0                                                   Maize starch paste (5% w/v aqueous paste)                                                             0.75                                                  Magnesium stearate      1.0                                                   (b) Tablet II           mg/tablet                                             Compound Z*             50                                                    Lactose Ph. Eur         223.75                                                Croscarmellose sodium   6.0                                                   Maize starch            15.0                                                  Polyvinylpyrrolidone (5% w/v aqueous paste)                                                           2.25                                                  Magnesium stearate      3.0                                                   (c) Tablet III          mg/tablet                                             Compound Z*             100                                                   Lactose Ph. Eur.        182.75                                                Croscarmellose sodium   12.0                                                  Maize starch paste (5% w/v aqueous paste)                                                             2.25                                                  Magnesium stearate      3.0                                                   (d) Capsule             mg/capsule                                            Compound Z*             10                                                    Lactose Ph. Eur.        488.5                                                 Magnesium stearate      1.5                                                   ______________________________________                                         Note                                                                          *The active ingredient Compound Z is a compound of formula I, or a salt       thereof, for example a compound of formula I described in any of the          preceding Examples.                                                      

The tablet compostions (a)-(c) may be enteric coated by conventionalmeans, for example, with cellulose acetate phthalate. ##STR2##

I claim:
 1. A compound of formula I:or a pharmaceutically acceptablesalt thereof, wherein: R¹ is hydrogen or hydroxy R² is hydrogen; or R¹and R² are joined together so that CR¹ --CR² is a double bond; X isselected from --CH₂ CH₂ --, --CH═CH--, --C≡C--, --CH₂ O--, --OCH₂ --,--CH₂ CO--, --COCH₂ --, --N═CH--, --CH═N--, --CH₂ S(O)_(n) -- and--S(O)_(n) CH₂ --, wherein n is 0, 1 or 2; Ar is an aromatic 5-memberedor 6-membered heterocyclic ring containing from one to three heteroatomsindependently selected from nitrogen, oxygen and sulphur, which ring isoptionally fused to a benzene ring; and wherein Ar may optionally beunsubstituted or may bear one or more substituents independentlyselected from halogeno, hydroxy, amino, nitro, cyano, carboxy,carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di- (1-6C)alkyl!amino, N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno-(1-6C)alkyl,(1-6C)alkanoylamino, ureido, N'-(1-6C)alkylureido, (1-6C)alkanoyl andoxime derivatives thereof and O-(1-6C)alkyl ethers of said oximederivatives; provided that when R¹ is hydroxy, X is not selected from--OCH₂ --, --N═CH-- and --S(O)_(n) CH₂ --, wherein n is 0, 1 or 2; andthat when R¹ and R² are both hydrogen, X is --CH₂ O--, --OCH₂ --, --CH₂S(O)_(n) -- or --S(O)_(n) CH₂ --, wherein n is 0, 1 or 2, then Ar is nota 5, 6 or 7 membered heteroaryl moiety.
 2. A compound of formula I:##STR3## or a pharmaceutically acceptable salt thereof, wherein: R¹ ishydroxyR² is hydrogen; or R¹ and R² are joined together so that CR¹--CR² is a double bond; X is selected from --CH₂ CH₂ --, --CH═CH--,--C≡C--, --CH₂ O--, --OCH₂ --, --CH₂ NH--, --NHCH₂ --, --CH₂ CO--,--COCH₂ --, --N═CH--, --CH═N--, --CH₂ S(O)_(n) -- and --S(O)_(n) CH₂ --,wherein n is 0, 1 or 2; Ar is an aromatic 5-membered or 6-memberedheterocyclic ring containing from one to three heteroatoms independentlyselected from nitrogen, oxygen and sulphur, which ring is optionallyfused to a benzene ring; and wherein Ar may optionally be unsubstitutedor may bear one or more substituents independently selected fromhalogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C) alkylamino, di-(1-6C)alkyl!amino, N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno-(1-6C)alkyl,(1-6C)alkanoylamino, ureido, N'-(1-6C)alkylureido, (1-6C)alkanoyl andoxime derivatives thereof and O-(1-6C)alkyl ethers of said oximederivatives; provided that when R¹ is hydroxy, X is not selected from--OCH₂ --, --NHCH₂ --, --N═CH-- and --S(O)_(n) CH₂ -- wherein n is 0, 1or
 2. 3. A process for preparing a compound of formula I, or apharmaceutically acceptable salt thereof, as claimed in claim 1 or 2,which process is selected from:(d) for those compounds of formula I inwhich X is --CH₂ CO--, reacting an organometallic compound of formulaAr--M in which M is a metal atom or a derivative thereof, with acompound of formula III; ##STR4## (i) for compounds of formula I inwhich X is --COCH₂ --, reacting a compound of formula Ar--CH₂ M in whichM is a metal atom or a derivative thereof, with a compound of formulaVII; ##STR5## (j) for those compounds of formula I in which X is --CH₂O-- or --CH₂ S--, reacting a compound of formula ArCH₂ Z¹ with acompound of formula VIII, in which Z¹ is a leaving group and Z² is --YM,or Z¹ is --YM and Z² is a leaving group, and wherein Y is oxygen orsulphur (as appropriate) and M is a metal atom; ##STR6## (n) for thosecompounds of formula I in which R¹ is hydroxy, R² is hydrogen and X ix--C≡C--, reacting a compound of formula Ar--C≡C--M in which M is a metalatom, with quinuclidin-3-one; (o) for those compounds in which R¹ and R²are hydrogen and X is --C≡C--, reacting a compound of formula Ar--C≡C--Min which M is a metal atom with a compound of formula VIII in which Z isa leaving group; ##STR7## (p) for those compounds in which X is --C≡C--,and R¹ is hydrogen or hydroxy and R² is hydrogen, reacting a compound offormula XI with a compound of formula Ar--Z in which Z is a leavinggroup in the presence of a catalyst; ##STR8## (q) for those compounds inwhich X is --CH═CH-- and R¹ is hydrogen or hydroxy and R² is hydrogen,reacting a compound of formula XII with a compound of formula Ar--Z inwhich Z is a leaving group in the presence of a catalyst; ##STR9## andwhereafter, when a pharmaceutically acceptable salt is required,treating the compound of formula I with an acid which affords aphysiologically acceptable anion or a base which affords aphysiologically acceptable cation.
 4. A method of inhibiting squalenesynthase in a warm-blooded animal (such as man) requiring suchtreatment, which method comprises administering to said animal aneffective amount of a compound of formula I: ##STR10## or apharmaceutically-acceptable salt thereof wherein: R¹ is hydrogen orhydroxyR² is hydrogen; or R¹ and R² are joined together so that CR¹--CR² is a double bond; X is selected from --CH₂ CH₂ --, --CH═CH--,--C.tbd.C--, --CH₂ O--, --OCH₂ --, --CH₂ NH--, --CH═N--, --N═CH--,--NHCH₂ --, --CH₂ CO--, --COCH₂ --, --CH₂ S(O)_(n) -- and --S(O)_(n) CH₂--, wherein n is 0, 1 or 2; Ar is a heterocyclic moiety containing fromone to three heteroatoms independently selected from nitrogen, oxygenand sulphur;and wherein Ar may optionally be unsubstituted or may bearone or more substituents independently selected from halogeno, hydroxy,amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C) alkenyl,(2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylamino, di- (1-6C)alkyl!amino,N-(1-6C)alkylcarbamoyl, di-N,N- (1-6C) alkyl!carbamoyl, (1-6C)alkoxycarbonyl, (1-6C) alkylthio, (1-6C) alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno-(1-6C) alkyl, (1-6C) alkanoylamino, (1-6C)alkanoyl and oxime derivatives thereof and O-(1-6C)alkyl ethers of saidoxime derivatives; provided that when R¹ is hydroxy, X is not selectedfrom --OCH₂ --, --NHCH₂ --, --N═CH-- and --SCH₂ --.
 5. A method oftreating cholesterol biosynthesis in a warm-blooded animal requiringsuch treatment, which method comprises administering to said animal aneffective amount of a compound of formula I, ##STR11## or apharmaceutically-acceptable salt thereof wherein: R¹ is hydrogen orhydroxyR² is hydrogen; or or R¹ and R² are joined together so that CR¹--CR² is a double bond; X is selected from --CH₂ CH₂ --, --CH═CH--,--C.tbd.C--, --CH₂ O--, --OCH₂ --, --CH₂ NH--, --CH═N--, --N═CH--,--NHCH₂ --, --CH₂ CO--, --COCH₂ --, --CH₂ S(O)_(n) -- and --S(O)_(n) CH₂--, wherein n is 0, 1 or 2; Ar is a heterocyclic moiety containing fromone to three heteroatoms independently selected from nitrogen, oxygenand sulphur;and wherein Ar may optionally be unsubstituted or may bearone or more substituents independently selected from halogeno, hydroxy,amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di- (1-6C)alkyl!amino,N-(1-6C)alkylcarbamoyl, di-N,N- (1-6C)alkyl!carbamoyl,(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, halogeno-(1-6C)alkyl, (1-6C)alkanoylamino,(1-6C)alkanoyl and oxime derivatives thereof and O-(1-6C)alkyl ethers ofsaid oxime derivatives; provided that when R¹ is hydroxy, X is notselected from --OCH₂ --, --NHCH₂ --, --N═CH-- and --SCH₂ --.
 6. A methodof treating hypercholesterolemia or atherosclerosis in a warm-bloodedanimal comprising administering to said animal an effective amount of acompound of formula I, ##STR12## or a pharmaceutically-acceptable saltthereof wherein: R¹ is hydrogen or hydroxyR² is hydrogen; or or R¹ andR² are joined together so that CR¹ --CR² is a double bond; X is selectedfrom --CH₂ CH₂ --, --CH═CH--, --C≡C--, --CH₂ --O, --OCH₂ --, --CH₂ NH--,--CH═N--, --N═CH--, --NHCH₂ --, --CH₂ CO--, --COCH₂ --, --CH₂ S(O)_(n)-- and --S(O)_(n) CH₂ --, wherein n is 0, 1 or 2; Ar is a heterocyclicmoiety containing from one to three heteroatoms independently selectedfrom nitrogen, oxygen and sulphur; and wherein Ar may optionally beunsubstituted or may bear one or more substituents independentlyselected from halogeno, hydroxy, amino, nitro, cyano, carboxy,carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di- (1-6C)alkyl!amino, N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno-(1-6C)alkyl,(1-6C)alkanoylamino, (1-6C)alkanoyl and oxime derivatives thereof andO-(1-6C)alkyl ethers of said oxime derivatives; provided that when R¹ ishydroxy, X is not selected from --OCH₂ --, --NHCH₂ --, --N═CH-- and--SCH₂ --.
 7. A compound as claimed in claim 1 or 2 wherein X isselected from --CH₂ CH₂ --, --CH═CH--, --C≡C-- --N═CH--, --CH═N--, --CH₂S(O)_(n) -- and --S(O)_(n) CH₂ --, wherein n is 0, 1 or
 2. 8. A compoundas claimed in claim 1 or 2 wherein Ar is selected from furyl, pyrrolyl,thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl,oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, benzfuranyl, quinolyl, isoquinolyl,benzimidazolyl, and indolyl.
 9. A compound as claimed in claim 1 or 2wherein Ar is selected from pyridyl and quinolyl.
 10. A compound asclaimed in claim 5 wherein Ar is selected from 6-butoxypyrid-3-yl,3-pyridyl, 5-bromopyrid-2-yl, 3-quinolyl, 2-quinoyl, 5-methylpyrid-2-yland 5-methoxycarbonylpyrid-2-yl.
 11. A compound as claimed in claim 1 or2 wherein X is --C≡C--.
 12. A compound as claimed in claim 1 or 2wherein Ar may optionally be unsubstituted or may bear one or moresubstituents independently selected from halogeno, hydroxy, nitro,(1-6C)alkyl, (2-6C)alkenyl, (1-6C)alkoxy, (1-6C)alkanoylamimo,halogeno(1-6C)alkyl, (1-6C)alkanoyl and oxime derivatives thereof andO(1-6C)alkyl ethers of said oximes.
 13. A compound which is selectedfrom:3- 2-(6-butoxypyrid-3-yl)ethynyl!quinuclidin-3-ol; 3-2-(3-pyridyl)ethynyl!quinuclidin-3-ol; 3-2-(6-bromopyrid-3-yl)ethynyl!quinuclidin-3-ol; 3-2-(3-quinolyl)ethynyl!quinuclidin-3-ol; 3-2-(2-quinolyl)ethynyl!quinuclidin-3-ol; 3-2-(5-methylpyrid-2-yl)ethynyl!quinuclidin-3-ol; 3-2-(5-methoxycarbonylpyrid-2-yl)ethynyl!quinuclidin-3-ol;and theirpharmaceutically acceptable salts.
 14. A pharmaceutical compositioncomprising a compound of formula I, or a pharmaceutically acceptablesalt thereof thereof, as claimed in claim 1 or 2 together with apharmaceutically acceptable diluent or carrier.